Immunological alterations may be used as ecotoxicological biomarkers to detect and monitor biological effects of chemical contaminants in polluted environments. This study reports on a survey of Pacific oysters from the Atlantic coast of Britanny (France) after the “Erika” oil spill. Reared stocks were sampled twice a year from November 2001 to March 2003 at three impacted sites and at an additional site outside the spill area. A multiparametric diagnosis of the immune system was performed on individual hemolymph samples to identify structural, immunopathological alterations and functional impairment of immunocompetent cells. One year after the spill, severe immunological alterations were observed in a site heavily impacted by oil. Since the oysters there had higher contents of PAH compared to the other sites, it was suggested that chronic contamination, possibly generated by oil trapped in the sediments, had induced immunotoxicity. Moreover, moderate variations in some hemolymph parameters observed at the non-impacted area strongly suggested that natural environmental factors may have generated physiological stress. An immunotoxicological index applied here in order to integrate all measurements of defense-related functions appeared to be an efficient tool to identify samples suffering immunological stress.